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Summary: Formamidopyrimidine-DNA glycosylase N-terminal domain

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Formamidopyrimidine-DNA glycosylase (Fpg) is a DNA repair enzyme that excises oxidised purines from damaged DNA. This family is the N-terminal domain contains eight beta-strands, forming a beta-sandwich with two alpha-helices parallel to its edges [1].

Internal database links

External database links

This entry represents the catalytic domain of DNA glycosylase/AP lyase enzymes, which are involved in base excision repair of DNA damaged by oxidation or by mutagenic agents. Most damage to bases in DNA is repaired by the base excision repair pathway [PUBMED:15588838]. These enzymes are primarily from bacteria, and have both DNA glycosylase activity (EC) and AP lyase activity (EC). Examples include formamidopyrimidine-DNA glycosylases (Fpg; MutM) and endonuclease VIII (Nei).

Formamidopyrimidine-DNA glycosylases (Fpg, MutM) is a trifunctional DNA base excision repair enzyme that removes a wide range of oxidation-damaged bases (N-glycosylase activity; EC) and cleaves both the 3'- and 5'-phosphodiester bonds of the resulting apurinic/apyrimidinic site (AP lyase activity; EC). Fpg has a preference for oxidised purines, excising oxidized purine bases such as 7,8-dihydro-8-oxoguanine (8-oxoG). ITs AP (apurinic/apyrimidinic) lyase activity introduces nicks in the DNA strand, cleaving the DNA backbone by beta-delta elimination to generate a single-strand break at the site of the removed base with both 3'- and 5'-phosphates. Fpg is a monomer composed of 2 domains connected by a flexible hinge [PUBMED:10921868]. The two DNA-binding motifs (a zinc finger and the helix-two-turns-helix motifs) suggest that the oxidized base is flipped out from double-stranded DNA in the binding mode and excised by a catalytic mechanism similar to that of bifunctional base excision repair enzymes [PUBMED:10921868]. Fpg binds one ion of zinc at the C terminus, which contains four conserved and essential cysteines [PUBMED:8473347, PUBMED:7704272].

Endonuclease VIII (Nei) has the same enzyme activities as Fpg above (EC, EC), but with a preference for oxidized pyrimidines, such as thymine glycol, 5,6-dihydrouracil and 5,6-dihydrothymine [PUBMED:15232006].

These protein contains three structural domains: an N-terminal catalytic core domain, a central helix-two turn-helix (H2TH) module and a C-terminal zinc finger [PUBMED:11912217]. The N-terminal catalytic domain and the C-terminal zinc finger straddle the DNA with the long axis of the protein oriented roughly orthogonal to the helical axis of the DNA. Residues that contact DNA are located in the catalytic domain and in a beta-hairpin loop formed by the zinc finger [PUBMED:12055620].

Gene Ontology

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Domain organisation

Below is a listing of the unique domain organisations or architectures in which
this domain is found.
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The graphic that is shown by default represents the longest sequence
with a given architecture. Each row contains the following information:

the number of sequences which exhibit this architecture

a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one Gla
domain, followed by two consecutive EGF domains, and
finally a single Trypsin domain

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Alignments

We store a range of different sequence alignments for families. As well
as the seed alignment from which the family is built, we provide the
full alignment, generated by searching the sequence database
(reference proteomes) using the
family HMM. We also generate alignments using four
representative proteomes (RP) sets, the UniProtKB sequence database,
the NCBI sequence database, and our metagenomics sequence database.
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There are various ways to view or download the sequence alignments that
we store. We provide several sequence viewers and a plain-text
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Alignment types

We make a range of alignments for each Pfam-A family:

seed

the curated alignment from which the HMM for the family is
built

full

the alignment generated by searching the sequence database
using the HMM

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an HTML-based representation of the alignment, coloured according to
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Downloading

You may find that large alignments cause problems for the viewers and
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View options

We make a range of alignments for each Pfam-A family. You can see a
description of each
above.
You can view these alignments in various ways but please note that some
types of alignment are never generated while others may not be available
for all families, most commonly because the alignments are too large to
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Seed(820)

Full(9797)

Representative proteomes

UniProt(26585)

NCBI(35945)

Meta(2216)

RP15(2198)

RP35(6355)

RP55(9930)

RP75(14039)

Jalview

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View

View

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View

View

View

HTML

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PP/heatmap

1

1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: available,
not generated,
— not available.

Format an alignment

Seed(820)

Full(9797)

Representative proteomes

UniProt(26585)

NCBI(35945)

Meta(2216)

RP15(2198)

RP35(6355)

RP55(9930)

RP75(14039)

Alignment:

Format:

Order:

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Sequence:

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HMM logos is one way of visualising profile HMMs. Logos provide a
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Trees

This page displays the phylogenetic tree for this family's seed
alignment. We use
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approximately-maximum-likelihood phylogenetic trees from our seed
alignment.

Curation and family details

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can see the definitions of many of the terms in this section in the
glossary and a fuller
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This chart is a modified "sunburst" visualisation of
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tree as a separate arc, arranged radially with the superkingdoms
at the centre and the species arrayed around the outermost
ring.

How the sunburst is generated

The tree is built by considering the taxonomic lineage of each
sequence that has a match to this family. For each node in the
resulting tree, we draw an arc in the sunburst. The radius of
the arc, its distance from the root node at the centre of the
sunburst, shows the taxonomic level ("superkingdom",
"kingdom", etc). The length of the arc represents
either the number of sequences represented at a given level, or
the number of species that are found beneath the node in the
tree. The weighting scheme can be changed using the sunburst
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In order to reduce the complexity of the representation, we
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only the following eight major taxonomic levels:

superkingdom

kingdom

phylum

class

order

family

genus

species

Colouring and labels

Segments of the tree are coloured approximately according to
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As you move your mouse across the sunburst, the current node
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If you pause over an arc, a tooltip will be shown, giving the
name of the taxonomic level in the title and a summary of the
number of sequences and species below that node in the tree.

Anomalies in the taxonomy tree

There are some situations that the sunburst tree cannot easily
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Missing taxonomic levels

Some species in the taxonomic tree may not have one or more of
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taurus is not assigned an order in the NCBI taxonomic tree.
In such cases we mark the omitted level with, for example,
"No order", in both the tooltip and the lineage
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Unmapped species names

The tree is built by looking at each sequence in the full
alignment for the family. We take the name of the species given
by UniProt and try to map that to the full taxonomic tree from
NCBI. In some cases, the name chosen by UniProt does not map to
any node in the NCBI tree, perhaps because the chosen name is
listed as a synonym or a misspelling in the NCBI taxonomy.

So that these nodes are not simply omitted from the sunburst
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these unmapped species, we show all levels between the
superkingdom and the species as "uncategorised".

Sub-species

Since we reduce the species tree to only the eight main
taxonomic levels, sequences that are mapped to the sub-species
level in the tree would not normally be shown. Rather than leave
out these species, we map them instead to their parent species.
So, for example, for sequences belonging to one of the
Vibrio cholerae sub-species in the NCBI taxonomy, we
show them instead as belonging to the species Vibrio
cholerae.

Too many species/sequences

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The tree shows the occurrence of this domain across different species.
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Species trees

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Unfortunately we have found that there are problems viewing the
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Interactive tree

For all of the domain matches in a full alignment, we count the
number that are found on all sequences in the alignment.
This total is shown in the purple box.

We also count the number of unique sequences on which each domain is
found, which is shown in green.
Note that a domain may appear multiple times on the
same sequence, leading to the difference between these two numbers.

Finally, we group sequences from the same organism according to the
NCBI
code that is assigned by
UniProt,
allowing us to count the number of distinct sequences on which the
domain is found. This value is shown in the
pink boxes.

We use the NCBI species tree to group organisms according to their
taxonomy and this forms the structure of the displayed tree.
Note that in some cases the trees are too large (have
too many nodes) to allow us to build an interactive tree, but in most
cases you can still view the tree in a plain text, non-interactive
representation. Those species which are represented in the seed
alignment for this domain are
highlighted.

You can use the tree controls to manipulate how the interactive tree
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highlight species that are represented in the seed alignment

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Interactions

There are
3
interactions for this family.
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We determine these interactions using
iPfam,
which considers the interactions between residues in three-dimensional
protein structures and maps those interactions back to Pfam families.
You can find more information about the iPfam algorithm in the
journal article that accompanies the website.

Structures

For those sequences which have a structure in the
Protein DataBank, we
use the mapping between UniProt, PDB and Pfam coordinate
systems from the PDBe group, to allow us to map
Pfam domains onto UniProt sequences and three-dimensional protein
structures. The table below
shows the structures on which the Fapy_DNA_glyco
domain has been found. There are 108
instances of this domain found in the PDB. Note that there may be
multiple copies of the domain in a single PDB structure, since many
structures contain multiple copies of the same protein sequence.